The purpose of this UM1 Cooperative Agreement is to support participation by a consortium of three National Cancer Institute (NCl)-Designated Cancer Centers in a consolidated, integrated NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN) to conduct early phase experimental therapeutics clinical trials. The Consortium of the City of Hope Comprehensive Cancer Center (COH, the Lead Academic Organization, [LAO]), The University of Southern California (USC)/Norris Comprehensive Cancer Center (USC, Associate Organization [AO]) and the University of California, Davis Cancer Center (UCD, AO) has a 20-year history as a multidisciplinary group conducting early phase experimental therapeutics clinical trials of NCI-Sponsored Investigational New Drugs (INDs) under UOl Cooperative Agreements and NOI Contracts. In addition to working within our own Consortium, we have developed collegial arrangements with other U01 and N01 holders to take advantage of their specific expertise and more efficiently complete clinical trials. Our consortium will contribute to ET-CTN agent-specific trans-network drug development teams from the combined expertise of COH, USC, and UCD in the areas of molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed early phase developmental and pharmacokinetic studies. These early phase studies will lead not only to the assignment of a recommended, biologically effective Phase II dose, and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that are directed against novel molecular pathways, but will also provide a mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related alterations of tumr and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanism of action of the compounds both in the laboratory and the clinic. As such, they will advance the ET-CTN overall goal to define better approaches to the development of novel anticancer agents that capitalize on the ability to characterize tumors molecularly and find appropriate biomarkers to select patients most likely to respond to specific agents.